Introduction: Ca2+/nuclear factor of activated T-cells (Ca2+/NFAT) signaling pathway may play a crucial role in Kawasaki disease (KD). Genes of Ca2+/NFAT signaling pathway have been reported mutated in KD children and the inhibitor of Ca2+/NFAT,cyclosporine A (CsA) has been used to treat KD children clinically. However, little is known about the molecular basis of NFAT involved in KD. Objective: We investigated the poorly understood Ca2+/NFAT regulation of coronary artery endothelial cells and the consequent dysfunction in KD pathogenesis. Methods: Sera from healthy, febrile and KD children were incubated with human coronary artery endothelial cells (HCAECs). KD–related NFATc1, NFATc3 and some inflammatory molecules were quantified using reverse transcriptase quantitative polymerase chain reaction and Western blotting. The function of endothelial cells was analyzed by CCK8, RTCA and tube formation assay. Results & Discussion: HCAECs stimulated with sera from KD children exhibited significant increases in proliferation and angiogenesis, increased level of NFATc1, NFATc3 and some inflammatory molecules (like E-selectin, VCAM-1, TF and MCP-1), compared stimulated with sera from healthy children and febrile children. NFATc1 and NFATc3 also displayed nuclear translocation. HCAECs stimulated with sera from KD patients treated with CsA showed remarkably decreased proliferation, angiogenesis, NFATc1 and inflammatory molecules levels as compared with results for untreated HCAECs (P= 0.0256, P= 0.0052, P=0.0253 and P= 0.0043, respectively). Conclusions: Our data reveals that KD sera activate the Ca2+/NFAT in HCAECs, leading to dysfunction and inflammation of endothelial cells. The cytoprotective effects of CsA treatment appear to ameliorate endothelial cell homeostasis via Ca2+/NFAT.